tbuckley/cabot-search huggingface dataset:
Long-term outcomes of phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early failure oral cancer.
Authors: Sachin Babanrao Dhumal, Vijay Maruti Patil, Vanita Noronha, Nandini Sharrel Menon, Kavita Prakash Nawale, Manoj Mahimkar, Kumar Prabhash
Journal: Journal of Clinical Oncology (2022)

e18021 Background: Triple metronomic chemotherapy is one of the options of treatment in platinum-refractory/early failure oral cancer. However long term outcomes with this regimen are unknown. Methods: Adult patients with platinum-refractory/early failure oral cancer were enrolled in the study. Patients were administered erlotinib 150 mg once daily celecoxib 200 mg twice daily and methotrexate weekly (phase 1 in variable dose 15-6 mg/m2 &amp; 9 mg/m2 in phase 2), all taken orally till progression of disease or development of intolerable adverse events. The primary objective was to estimate the long term overall survival and factors impacting it. Kaplan Meier method was used for time to event analysis. COX proportional hazard model was used to identify factors impacting OS and PFS. The factors included in the model were age, gender, ECOG PS, tobacco exposure, a subsite of primary and circulating endothelial cell levels at baseline. A p-value of 0.05 was considered significant. Results: A total of 91 patients were recruited (15 in phase 1 &amp; 76 in phase 2), the median follow-up was 41 months and 84 events of death had occurred. The median OS was 6.67 months (95%CI 5.43-7.37). The 1-year, 2-years and 3-years OS were 14.07% (95%CI 7.75-22.2), 5.86% (95%CI 2.18-12.2) and 5.86% (95%CI 2.18-12.2) respectively. The only factor favourably impacting OS was the detection of circulating endothelial cells at baseline (HR = 0.459; 95%CI 0.28 -0.753, P = 0.002). The median PFS was 4.3 months (95%CI 4.1-5.1) and the 1-year PFS was 12.97% (95%CI 6.8-21.2). The factors with statistically significant impact on PFS were detection of circulating endothelial cells at baseline (HR = 0.479; 95%CI 0.3 -0.775, P = 0.002) and tobacco exposure at baseline (HR = 0.505; 95%CI 0.272 -0.937, P = 0.03). Conclusions: The long term outcomes with triple oral metronomic chemotherapy with erlotinib, methotrexate and celecoxib are unsatisfactory. Detection of circulating endothelial cells at baseline is a biomarker predicting efficacy of this therapy. Clinical trial information: CTRI/2016/04/006834..
Comprehensive genomic profiling: Insights into diagnostic value and treatment strategy.
Authors: Michelle Shiller, Haiying Zhang, Lihui Yin, Sandeep Mukherjee, Christopher Coldren, Robert Gary Mennel, Kartik Konduri, David Wood, Pranil Chandra
Journal: Journal of Clinical Oncology (2022)

e15028 Background: The clinical application of next-generation sequencing (NGS) has continued to advance precision oncology by enabling the identification of biomarkers that may predict potential response to targeted therapy, yet the benefit of tissue-based NGS to patient care is not solely confined to this narrow application. Not uncommonly, NGS can reveal genomic characteristics of the tumor that may be inconsistent with initial pathology review and clinical presentation. When this occurs, these genomic insights along with other clinical and diagnostic findings may be utilized to reconsider the initial diagnosis and seek to explore alternative diagnostic explanations that may be more consistent with the genomic findings. Methods: Patient diagnoses and clinical data were reviewed and compared against NGS results to determine if the genomic profile was consistent with and supports the initial diagnosis. If the genomic profile of the tumor was found to be inconsistent with the initial diagnosis, a secondary review of the case was initiated. Out of a cohort of &gt;2,500 patient cases, notable examples of cases were identified that highlight the impact of NGS findings on the diagnostic classification of the tumor. Genomic profiling was conducted utilizing PathGroup’s molecular pathology-directed tumor profiling solution, Endeavor, which is powered by the FDA-cleared PGDx elio tissue complete test. Results: Among the identified patient cases where initial pathological diagnosis was altered following review of NGS results, several examples include 1) a sarcoma case being re-classified as melanoma, 2) a lung lesion initially diagnosed as NSCLC that was metastatic basal cell carcinoma and 3) a cancer of unknown primary that was determined to be a cholangiocarcinoma. Treating oncologists were kept apprised of all diagnostic findings and modifications to either the initial diagnosis or to the tumor classification which led to an altered treatment strategy in each case. Conclusions: NGS can be broadly applied throughout the cancer care continuum, with a new perspective on its potential value diagnostically. In these cases, re-evaluation and subsequent re-classification led to treatment strategy shifts that are more specific to the patient’s tumor type. These findings provide critical real-world evidence that supports the value of broad genomic profiling in complex cancer cases, especially when the genomic findings are inconsistent with the initial diagnosis, or the diagnosis is unclear.
Investigation of<i> CREBBP </i>mutation and correlation with immunotherapy biomarker in Chinese bladder cancer patients.
Authors: Junyong Chen, Xue Hu, Yating Zheng, Mengli Huang
Journal: Journal of Clinical Oncology (2022)

e16537 Background: The CREBBP gene provides instructions for making CREB binding protein, is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. Previous research on CREBBP gene revealed that CREBBP is correlated with tumor occurrence and the efficacy of immune checkpoint inhibitors (ICIs) through directly regulate DNA damage response (DDR) pathway. However, the CREBBP characteristics, its correlation with immunogenic marker, and the predictive value of immunotherapy in bladder cancer was unknown. Methods: An independent cohorts (the MSKCC study cohort) with next generation sequencing (NGS) data from 211 patients with bladder cancer of pan-cancer, which were used to analyze the prognostic effect of CREBBP on immunotherapy. Tumor tissue samples from Chinese bladder cancer were analyzed using NGS (panel on 381/733-gene). TMB was defined as total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Estimation of immune filtration cells scores were conducted via TIMER2.0. Results: In MSKCC cohort, there were 30 (14.2%) patients harbored CREBBP mutation ( CREBBP mut ), and it (median, 15.71 Muts/Mb) was associated with higher TMB (P ＜0.0001) than the wild-type ( CREBBP wt ) (median, 7.81 Muts/Mb). In terms of prognostic effect with ICIs therapy, there was significant difference on overall survival (OS) (HR = 0.43; 95% CI, 0.21–0.90; P = 0.02) between CREBBP mut (median, 12 months) and CREBBP wt (median, 8 months). In Chinese patients, genetic mutation of 184 bladder cancer patients were analyzed with NGS and 24 (13.0%) harbored CREBBP mut , similar to western patients of the MSKCC cohort. In bladder cancer patients with CREBBP mut , the most frequently co-mutated genes were TP53 (71%), followed by ATM (46%), BLM (42%), and BRCA1 (29%). CREBBP mut (median, 15.10 Muts/Mb) was associated with higher TMB (P = 0.0008) than CREBBP wt (median, 9.50 Muts/Mb), which was significant difference. Similarly, there was significant difference in MSI between CREBBP mut and CREBBP wt (P = 0.0095). However, there was no difference in PD-L1 expression between the two groups (P = 0.53). In the immune microenvironment of TCGA-SKCM cohort, only CD4 + T cell (P = 0.022) and activated NK cell (P = 0.042) were significantly higher in CREBBP mut patients. Conclusions: The results showed that the CREBBP gene had a high correlation with TMB and MSI in bladder cancer, and might a potential biomarker for ICIs therapy.
Efficacy of niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer in phase 3 PRIME study: A subgroup analysis by response to first-line platinum-based chemotherapy.
Authors: Rutie Yin, Ning Li, Lingying Wu, Jing Wang, Jianqing Zhu, Lingya Pan, Beihua Kong, Hong Zheng, Jihong Liu, Xiaohua Wu, Li Wang, Yi Huang, Ke Wang, Dongling Zou, Hongqin Zhao, Chunyan Wang, Weiguo Lu, Xiaoa Zhen, Wenzhao Hang, Jianmei Hou
Journal: Journal of Clinical Oncology (2022)

5551 Background: In PRIME (NCT03709316), niraparib significantly reduced the risk of disease progression or death versus placebo (PBO) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.34–0.60) in Chinese patients (pts) with newly diagnosed, advanced ovarian cancer (OC), regardless of biomarker status. As response to chemotherapy is deemed to be associated with prognosis in OC, this subgroup analysis of the PRIME study aims to better understand niraparib treatment effect in pts based on response to first-line platinum-based chemotherapy (1L CT). Methods: This randomized, double-blind, PBO-controlled, phase 3 trial enrolled adults with newly diagnosed, stage III or IV OC who achieved a complete response (CR) or partial response (PR) to 1L CT and received primary or interval cytoreductive surgery, irrespective of residual disease status after surgery. Pts were randomized (2:1) to receive niraparib or PBO, whose starting doses were individualized based on baseline bodyweight and platelet count, with stratification according to status of germline BRCA mutations (yes or no), tumor homologous recombination status (deficient or proficient), receipt of neoadjuvant chemotherapy (yes or no), and clinical response to 1L CT (CR or PR). This prespecified exploratory analysis reports progression-free survival (PFS) and HRs based on clinical response to 1L CT. The data cut-off date was 30 September 2021. Results: Of the 384 pts randomized, 315 (82.0%) and 69 (18.0%) had a CR (212 niraparib, 103 PBO) or PR (43 niraparib, 26 PBO) to 1L CT, respectively. Baseline characteristics are presented in the Table. The overall PFS median follow-up was 27.5 months. Niraparib significantly extended PFS compared with PBO: the median PFS was 29.4 months for niraparib versus 8.3 months for PBO (HR=0.45; 95% CI, 0.32–0.61; P&lt;0.001) in the CR group and was 19.3 months for niraparib versus 8.3 months for PBO (HR=0.45; 95% CI, 0.23–0.86; P=0.014) in the PR group. Conclusions: In pts with newly diagnosed advanced OC, PFS was substantially prolonged with niraparib versus PBO, regardless of response to chemotherapy and biomarker status. Moreover, pts who achieved a CR appeared to receive larger PFS benefit from niraparib than those with a PR. Clinical trial information: NCT03709316. [Table: see text]
Micro-organospheres retain patient tumor microenvironment for precision immuno-oncology.
Authors: Shengli Ding, Naveen R. Natesh, Kassandra Spiller, Rui Xi, Daniel Nelson, Nikolche Gjorevski, Antje Walz, Estelle Marrer-Berger, Hans Clevers, Shiaowen David Hsu, Xiling Shen
Journal: Journal of Clinical Oncology (2022)

2573 Background: Current patient-derived organoid (PDO) models are largely devoid of immune components. We developed a precision microfluidic and membrane platform to generate patient-derived micro-organospheres (MOS) that retain tumor-resident immune and stromal components for personalized immuno-oncology (IO) assays. Methods: MOS were generated from lung, kidney, and colorectal cancer patients. The composition and function of patient tumor-resident immune cells in MOS were characterized by flow cytometry, single-cell RNA-seq, antibody staining, and TCR-seq. High-content and longitudinal imaging with AI analyses were used to quantify tumor cell death and immune cell dynamics inside MOS in response to IO therapies including checkpoint inhibitors, T cell bispecific antibodies, and adoptive tumor infiltrating lymphocyte (TIL) therapies, followed by single-cell analyses. Results: Tumor and stromal cells quickly form tissue niches inside MOS to sustain the viability and function of encapsulated immune cells. MOS derived from lung and kidney cancer patients respond to Nivolumab, indicated by the Annexin V apoptosis marker. ESK1* (TCB antibody targeting HLA-A2/WT1) induces killing in eight lung tumor patients derived MOS. We further developed a MOS T-cell potency assay as autologous TILs or PBMC efficiently infiltrate MOS from lung, kidney and CRC patients and induce tumor cell apoptosis. Adjunctive therapies combining TCB with TILs enhanced the potency of adoptive cell therapy against lung tumor. Based on the data, three ongoing and upcoming personalize IO clinical trials will further validate the ability of the MOS assay to predict patient response to TCB, checkpoint combinations, and adoptive cell therapy. Conclusions: MOS provide a rapid and scalable personalized platform for developing and testing IO therapies such as checkpoint inhibitors, bispecific antibodies, and T cell therapies on patient tumor models that still retain the original tumor microenvironments.
Defining a prognostic risk score in ovarian cancer patients by integrated analysis of serum mesothelin, HE4, CA125 and surgical outcome.
Authors: Pauline Wimberger, Daniel Klotz, Maren Göckenjan, Theresa Link, Jan Dominik Kuhlmann
Journal: Journal of Clinical Oncology (2022)

e17611 Background: In ovarian cancer, serum CA125 is currently the only biomarker used in routine clinical practice and has several limitations, e.g. it is not entirely specific for ovarian malignancy. Alternative serum biomarkers have been proposed for ovarian cancer, such as mesothelin or human epididymis protein 4 (HE4). Although it is known that single marker analysis is often insufficient for diagnostic purposes or relapse prediction, no comprehensive studies on the combination of these markers have been conducted, yet. Using a multi-marker prediction model, we herein investigated the clinical usefulness of mesothelin and HE4, detected in a sequence of pre- and post-operative serum samples, in complementing the standard marker CA125. Methods: Serum mesothelin, HE4 and CA125 were quantified by Lumipulse G chemiluminescent enzyme immunoassay (Fujirebio) in a total of 432 serum samples from 90 healthy controls and 192 ovarian cancer patients (thereof 81.8% with FIGO III/IV), including 151 paired pre- and post-operative samples. Results: Pre-operative serum mesothelin and HE4 were significantly elevated compared to healthy controls with a median ratio (IQR) to controls of 2.6 and 9.6, respectively (p &lt; 0.0001). High pre-operative levels of mesothelin or HE4 alone were significantly correlated with advanced FIGO-stage (p &lt; 0.0001) and predicted surgical outcome (p &lt; 0.0001). We retrospectively compiled mesothelin and HE4 levels with CA125, BRCA mutational status and surgical outcome, in order to define a multi-marker setting. Both, mesothelin and HE4 levels were independent from BRCA mutational status, however they positively correlated with CA125. Detection of pre-operative HE4 &gt; 498pM (OR = 4.1, p &lt; 0.0001) combined with pre-operative CA125 &gt; 516U/mL (OR = 2.2, p = 0.001) was the best combination to predict surgical outcome (AUC = 0.815). Finally, we defined a prognostic signature, including pre-operative CA125, post-operative mesothelin, HE4 and surgical outcome, which was superior to the individual prognostic capacity of all included parameters. Our model allowed the calculation of a weighted risk score, stratifying patient at “lower risk” (score 0-4) or at “higher risk” (score 5-10). Patients with higher risk had significantly shorter PFS (19.0 months (95%CI = 16.1-21.8) vs 64.1 months (95%CI = 56.8-71.3) p &lt; 0.0001) and OS (34.0 months (95%CI = 28.6-39.3) vs 71.2 months (95%CI = 64.6-77.7) p &lt; 0.0001). Conclusions: This is the first study, proposing an integrated prognostic risk score for ovarian cancer patients, which could easily be implemented into routine diagnostics and may guide personalized treatment decisions. Patients at “higher risk”, as identified by this model, could potentially benefit from an intensified therapy regime, whereas patients at “lower risk” might be suitable for treatment de-escalation.
Bevacizumab combined with platinum-based chemotherapy in patients with primary or relapsed ovarian cancer: Meta-analysis and literature review.
Authors: Faith Abodunrin, Abubakar Tauseef, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2022)

5582 Background: Epithelial ovarian cancer has the highest mortality rates among all gynecological malignancies and is the fifth leading cause of cancer-related deaths in females. Previously, the treatment of ovarian cancers included cytoreductive surgery in combination with platinum-based chemotherapy. While this treatment regimen initially resulted in a good response, most of the patients subsequently relapsed. Given the role of Vascular Endothelial Growth factor (VEGF) and angiogenesis in the progression of ovarian cancer, VEGF inhibitors such as Bevacizumab were considered in the treatment of advanced or relapsed ovarian cancer patients. We conducted a meta-analysis to compare the efficacy of Bevacizumab with platinum-based chemotherapy to platinum-based chemotherapy. Methods: A thorough systematic literature review identified five eligible studies reporting the efficacy of bevacizumab with platinum-based chemotherapy in the treatment of advanced or recurrent Ovarian cancer as compared to control group receiving platinum-based chemotherapy alone. These studies were randomized Phase III clinical trials, one of which was recently published in 2021. Summary estimates of the clinical endpoints were calculated with risk ratio (RR) and 95% confidence intervals using the random-effects model. Heterogeneity between studies was examined with COCHRAN’S Q based 12 statistics. The primary endpoint was progression free survival at 12 months while secondary endpoints were overall survival and certain adverse effects. Results: Our pooled analysis from the five studies included 4,648 patients. 2,641 were in the Bevacizumab and platinum-based treatment group while 2007 patients in sole-platinum based chemotherapy group. There was a statistically significant difference in primary outcome of progression free survival at 12 months was noted (RR = 1.56 (95% CI: 1.09 to 2.24; p = 0.020). 33,4% of patients in the treatment group as compared to 22.9% observed in the control group attained PFS at 12 months. The secondary outcome of overall survival at 12 months was seen in 76.7% patients in treatment group as compared to 73.02% observed in control group. This was no statistically significant difference in this case (RR = 1.04 (95% CI: 0.96 to 1.12; p = 0.34). Adverse effects including hypertension, proteinuria, arterial and venous thromboembolism, posterior reversible leukoencephalopathy syndrome occurred more frequently in the treatment group. Conclusions: Results from our meta-analysis support the superiority of Bevacizumab with platinum-based chemotherapy over platinum-based chemotherapy with regards to PFS. However, the OS benefit remains questionable.
A phase 1b lead-in to a randomized phase 2 trial of lurbinectedin plus doxorubicin in leiomyosarcoma (LMS).
Authors: Gregory Michael Cote, Edwin Choy, Katherine Anne Thornton, Emanuele Mazzola, Sara Bouberhan, Priscilla Merriam, Andrew J. Wagner, Jeffrey A. Morgan, Candace L. Haddox, Jay Oza, George D. Demetri, Suzanne George
Journal: Journal of Clinical Oncology (2022)

TPS11592 Background: Single agent or combination chemotherapy regimens, typically including doxorubicin or gemcitabine, represent standard of care options for first- and second-line therapy in patients (pts) with metastatic LMS. However, response rates (ORR) and progression-free (PFS)/overall survival (OS) remain poor. Lurbinectedin (PharmaMar S.A. and Jazz Pharmaceuticals) uniquely binds DNA, inducing DNA double strand breaks leading to apoptosis and delaying progression through phase S/G2 of the cell cycle. Lurbinectedin is a novel structural analog of trabectedin with improved toxicity profile, potency, and pharmacokinetics. In a prior pilot study, we showed that the combination of lurbinectedin and doxorubicin (L+D) was safe, with early signs of clinical activity, particularly in LMS. Thus, we designed this investigator-initiated/investigator-sponsored phase 1b lead-in to optimize doses of L+D, to be followed by a randomized (1:1) phase 2 study of L+D versus doxorubicin monotherapy in anthracycline-naïve LMS. Methods: Pts age &gt; 18 years with locally advanced or metastatic, unresectable LMS (non-GIST soft-tissue sarcoma histologies allowed in Phase 1b), without prior anthracycline or lurbinectedin/trabectedin, ECOG PS &lt; 3, measurable disease by RECIST 1.1, and normal organ function, are eligible. Phase 1b dosing will include a fixed dose of lurbinectedin and two dose levels of doxorubicin. The Phase 1b lead-in follows a standard 3+3 design where dose escalation will occur if 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted every two cycles. Once the recommended phase 2 dose (RP2D) is confirmed, Phase 2 will be initiated. Fifty pts will be randomized 1:1 including doxorubicin +/- lurbinectedin. Randomization will be stratified by uterine v. non-uterine origin of LMS. Pts progressing on single agent doxorubicin will be allowed to cross over to lurbinectedin monotherapy. The Phase 2 primary endpoint is PFS. Secondary endpoints include disease control rate, ORR, OS, PFS2 (for doxorubicin monotherapy patients who cross to lurbinectedin monotherapy). Archival tumor, germline DNA, and ctDNA will be collected for correlative studies exploring genomic markers of sensitivity/resistance. We will provide respective point estimate along with 90% confidence interval for each of the arms. Log-rank test will be performed to test the difference in survival (both PFS and OS) between groups. Regression analyses of survival data will be based on the Cox proportional hazards model. The first pt in dose-level 1 of the Phase 1b lead-in was enrolled in February 2022. Clinical trial information: NCT05099666.